A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy

National Institute of Neurological Disorders and Stroke (NINDS), Hugo W. Moser Research Institute at Kennedy Krieger, Inc., ALD Connect, Inc.

In this pilot study, the investigators will assess the safety of two high-dose regimens of oral vitamin D supplementation and measure the effects of vitamin D supplementation on markers of oxidative stress and inflammation in the blood and brain of study participants before, during, and after taking vitamin D supplements. The goal of the study is to establish research measures (i.e. biomarkers) and an optimal dose for vitamin D supplementation in boys with the X-linked adrenoleukodystrophy (ALD) genotype.

Prior research suggests that higher vitamin D levels in the blood are associated with reduced brain inflammation among individuals with multiple sclerosis, a disease that is similar to the cerebral demyelinating form of ALD. However, serious side effects (e.g. hypercalcemia, kidney stones) can occur if vitamin D levels get too high. The current study is designed to establish a safe dose of vitamin D for boys with ALD. Although the doses chosen for this study are expected to be safe, the investigators will monitor participants for early signs of vitamin D-related toxicity. The investigators will also examine whether or not vitamin D supplementation affects markers of oxidative stress and inflammation in the blood and brains of ALD boys. The study requires participants to agree to at least one year of participation. Participants will be asked to take a vitamin D supplement every day, submit blood for analysis every 3 months in the first year, and visit their study center (Stanford University or the Kennedy Krieger Institute) every 6 months throughout the period of study. Participants will be assigned a vitamin D dose based on bodyweight at entry. Starting doses will include 1,000 or 2,000 international units (IU) of vitamin D3 daily for a 6 month period, followed by a conditional increase to 2,000, 3,000, or 4,000 IU daily thereafter if vitamin D levels have not achieved a target threshold. The vitamin D supplements will be provided by the study. In keeping with the current standard of care for ALD boys aged 18mos - 25 years, participants will need to visit the study site every six months in order to complete a clinic visit and MRI of the brain with gadolinium. As part of this study, however, participants' will need to submit blood work every 3 months during the first year in order for the study investigators to ensure that the participants' calcium and vitamin D levels are in a safe range and to study the effects of vitamin D on markers in the blood. The MRI protocol during the first year will also include one additional sequence (magnetic resonance spectroscopy) in order to measure brain metabolites. The data generated from this study are intended, in part, to help design a future, large-scale clinical trial to determine whether vitamin D supplementation is capable of reducing the risk of developing the cerebral demyelinating form of ALD.

Leukodystrophy, ABCD1, Demyelination, Inflammation, ALD, Vitamin D, Oxidative Stress, X- linked, Adrenoleukodystrophy

Single-arm, dose-escalation starting at 1,000 IU or 2,000 IU of vitamin D3 daily for a 6 month period, followed by a conditional titration up to 4,000 IU daily for at least 6 months thereafter. No placebo.

Percent of patients with a plasma 25-OH vitamin D level in the target range (40-80ng/ml) at 12 months

The investigators expect 100% of patients will be in the target range at 12 months (i.e. oral dose of 4000 IU daily)

The investigators expect that 80% of patients will be in the target range 6 months (i.e. oral dose of 2000 IU daily)

Correlation between appearance of gadolinium enhancing brain lesion on MRI and most recent plasma 25-OH vitamin D level

For participants developing gadolinium enhancing lesions on MRI, the investigators will compare the most recent preceding 25-OH vitamin D level with the average 25-OH vitamin D level of participants in the study who did not develop gadolinium enhancing lesions. The investigators expect the development of gadolinium enhancing lesion on MRI will correlate with lower vitamin D levels. However, our current study is not sufficiently powered to measure this effect.

Brain MRI at baseline, 6, 12, 18, 24, 30, and 36 months study enrollment. Plasma 25-OH vitamin D levels at baseline, 3, 6, 9, 12, 18, 24, 30, 36 months of enrollment.

The investigators expect a decrease in whole blood protein carbonyl levels between baseline and 12 months.

Correlation between plasma 25-OH vitamin D and intracellular glutathione levels in peripheral monocytes

The investigators will use flow cytometry to measure intracellular GSH in CD14+ monocytes from participants peripheral blood at baseline and 12 months. The investigators will measure plasma 25-OH vitamin at the same time points. The investigators expect a positive correlation between plasma vitamin D levels and monocyte GSH levels.

The investigators expect a positive correlation between plasma 25-OH vitamin levels and GSH levels in whole blood (measured by tandem mass spectroscopy).

The investigators will examine the correlation between 25-OH vitamin D levels in plasma and total GSH levels in occipital white matter (measured by single-voxel MR spectroscopy).

The investigators do not expect any participants to develop hypercalcemia (serum calcium >10.7mg/dl) or related serious adverse events (e.g. kidney stones) while taking 2000 IU or 4000 IU daily.

Criteria for enrollment to screening: Molecular confirmation of X-linked ALD (VLCFA elevation & ABCD1 mutation) known in patient or immediate family member) Male Age 1.5yrs (i.e. 18mos) - 25yrs at screening Criteria for assignment to drug: Plasma 25-hydroxy vitamin D level ≤ 60ng/ml in past 30 days MRI brain in past 6 months that is negative for evidence of active cerebral demyelination Exclusion Criteria: history of liver or kidney disease history of nephrolithiasis history of hyperthyroidism history of ulcerative colitis, Crohn's disease, celiac disease taking medication interfering with gastrointestinal absorption contraindication or inability to complete MRI every 6 months